Thomas Gresham, the hotel's founder, was a foundling child, abandoned on the steps of the Royal Exchange, London.

He was named for the founder of that institution, Sir Thomas Gresham, a famous merchant-politician in the Elizabethan era.

In 1817, Gresham left Beauman's household and purchased two adjoining Georgian townhouses at 21 and 22 Sackville Street (now O'Connell Street), combining them into a lodging house he named Gresham's Hotel, catering mostly to the wealthy aristocracy and MPs who passed through Dublin on their way to London.

During the Irish Civil War, the Gresham was occupied by Anti-treaty forces under the command of Cathal Brugha and Countess Markievicz.

[6] The new structure was designed by English architect Robert Atkinson[3] and his business partner Alexander Frederick Berenbruck Anderson in a blend of the Art Deco and neo-classical styles.

[9] In January 2018 Dublin City Council set about rehoming 14 homeless families that had been living at The Gresham to allow for the refurbishment of a number of bedrooms and suites at the hotel.